The US Food and Drug Administration (FDA) has issued a revised draft guidance setting forth FDA’s views on the dissemination of certain information regarding “off-label” uses of drugs or medical devices. While the FDA has sought to clarify its position on manufacturer distribution of scientific and medical publications that include information on unapproved new uses of the manufacturer’s products, there are concerns within the life sciences industry and its representatives that, among other issues, the proposed guidance is overly burdensome and may trammel unlawfully upon manufacturers’ free speech rights.
The Revised Draft Guidance
Earlier this year, FDA issued, and solicited public comment on, a revised draft guidance entitled “Distributing Scientific and Medical Publications on Unapproved New Uses—Recommended Practices” (the “Draft Guidance”). See 79 Federal Register 11793 (3 March 2014). Revising a 2009 guidance, the Draft Guidance reflects FDA’s current thinking on recommended practices for drug and/or medical device manufacturers distributing to health care professionals or entities various materials—including scientific or medical journal articles, scientific or medical reference texts, or clinical practice guidelines (CPGs)—that discuss unapproved new uses, or “off-label” uses, for approved drugs or approved/cleared medical devices marketed in the US.
The Draft Guidance recognises “the value to health care professionals of truthful and non-misleading scientific or medical publications on unapproved new uses,” while still cautioning that information about off-label use is “in no way a substitute for the FDA premarket review process, which allows FDA to be proactive, rather than reactive, in protecting the public from unsafe or ineffective medical products.” Because scientific and medical information concerning the safety or effectiveness of a medical product’s unapproved new use often is published in scientific or medical journal articles, scientific or medical reference texts, and/or in CPGs, FDA has offered various recommendations regarding how off-label use information might be distributed through these channels. It is unlawful for a manufacturer to introduce a drug with an intent that it be used for an off-label purpose. To the extent that a manufacturer disseminates information about a product’s off-label use in accordance with the recommendations of the Draft Guidance, however, FDA does not intend to use that dissemination as evidence of the manufacturer’s intent that the product be used for an unapproved new use.
Some of the key recommendations of the Draft Guidance include:
- Scientific or medical journal articles: Summarised briefly, a scientific or medical journal article that includes information on unapproved uses and is distributed by a manufacturer should be peer-reviewed. Amongst other things, these materials should be disseminated with the approved/cleared labeling for each of the manufacturer’s products that is included in the distributed article; with a comprehensive bibliography of publications discussing adequate and well-controlled clinical studies published in scientific journals, medical journals, or scientific texts about the use of the drug or medical device; and with a representative publication that reaches contrary or different conclusions regarding the unapproved use—especially when the conclusions of the articles to be disseminated have been specifically called into question by another publication. They also should be accompanied by a prominently displayed and permanently affixed statement disclosing, among other items, all significant risks or safety concerns associated with the unapproved use of the product that are known to the manufacturer but not discussed in the article, and that some or all uses of the manufacturer’s product described in the information have not been approved or cleared by FDA.
- Scientific or medical reference texts: Where a reference text is distributed in its entirety but one or more individual chapters thereof devote “primary substantive discussion” to an individual product of the manufacturer distributing it, the reference text should be disseminated with, amongst other things, the approved/cleared product labeling for each such product. If, in lieu of an entire scientific or medical reference text, a manufacturer distributes an individual chapter or chapters that include information on unapproved/uncleared uses of the product, the chapter(s) should be unaltered/unabridged and extracted directly from the scientific or medical reference text in which it appears, and when necessary to provide context, be disseminated with other unaltered/unabridged chapters extracted directly from the same scientific or medical reference text (such as chapters that provide related or supportive information), and also be disseminated with the approved/cleared labeling for each of the manufacturer’s products that are included in the distributed chapter(s). The FDA also recommends that the reference text or chapter prominently display and permanently affix a statement containing, among other things, the disclosures approved for scientific/medical journal articles.
- Clinical practice guidelines (CPGs): CPGs are statements that include recommendations intended to help clinicians make decisions for individual patient care, including in circumstances where there are few or no approved drugs or devices indicated for the condition or the approved therapies have not proven successful for the individual. Ultimately, manufacturers wishing to disseminate CPGs that discuss unapproved/uncleared new uses of products should disseminate only those guidelines that are “trustworthy,” as defined by Institute of Medicine standards. Where a CPG is distributed in its entirety but one or more individual sections of that CPG devotes “primary substantive discussion” to an individual product of the manufacturer distributing it, it should be disseminated with the approved/cleared product labeling for each such product. And, if in lieu of an entire CPG, a manufacturer distributes an individual section or sections that include information on unapproved/uncleared uses, the section(s) should emanate from a “trustworthy” CPG and be unaltered/unabridged and extracted directly from the CPG in which it appears, and when necessary to provide context, be disseminated with other unaltered/unabridged sections extracted directly from the same CPG (such as sections which provide related or supportive information), and be disseminated with the approved/cleared labeling for each of the manufacturer’s products that are included in the distributed section(s). Prominent/permanent affixtures, similar to those discussed above, are also recommended.
Whatever the medium, FDA continually emphasises that any statements regarding off-label use must not be false or misleading, nor contain information recommending or suggesting a use of the product that would make it dangerous to health when used in the manner suggested.
Is “Free Speech” Muzzled?
Stakeholders have submitted comments on various issues arising out of the Draft Guidance. Among the issues raised was a concern that the Draft Guidance’s many restrictions regarding distribution of publications about off-label use may stop, or at least discourage, manufacturers from communicating with health care professionals about such uses. Thus, certain stakeholders have cautioned, the Draft Guidance may unlawfully restrict a manufacturer’s right, under the First Amendment to the US Constitution, to communicate accurate and beneficial information. One public policy advocate argued, for example, that while FDA can impose reasonable standards on off-label communications, the agency may not prohibit dissemination of peer-reviewed journal articles “unless it has very good reason to believe that the study being reported is of absolutely no scientific value.” See Comments of Washington Legal Foundation (WLF) to US FDA, submitted 15 May 2014. Also problematic are the Draft Guidance’s disclaimer requirements, which the advocate deemed “so burdensome that they become de facto prohibitions against dissemination.” Id. Thus, while it is fair for FDA to require a journal article to be disseminated with approved labeling, per advocates there is “no justification” for mandating a company to prepare a “comprehensive bibliography” and to attach all articles reaching “different conclusions,” and indeed this unduly burdensome requirement may well chill truthful, and constitutionally-protected, speech. Id.
Stakeholders have urged FDA to revise its recommendations to ensure that they do not violate free speech rights. Suggestions to FDA include (1) eliminating any reference to “adequate and well-controlled clinical investigation” as that would likely will be interpreted as significantly limiting the types of journal articles that could be disseminated; (2) narrowing the disclaimer requirements (including the requirement that a comprehensive bibliography and contrary articles/texts accompany each disseminated article); and (3) reducing the limitations imposed on dissemination of medical texts, particularly individual chapters. See id. Without such changes, it would be “virtually impossible” (as WLF urged) for manufacturers to distribute reprints and still comply with the Draft Guidance. Id.
FDA is currently considering these and other stakeholder comments as it works to finalise the Draft Guidance. It remains to be seen whether and/or to what extent FDA will specifically address free speech considerations and/or revise language in the final guidance in light of these and other stakeholder concerns. From a free speech perspective, the challenge will be to strike the proper balance between imposing reasonable and appropriate standards while allowing for the free flow of truthful information to health care professionals regarding off-label uses of FDA-regulated products.